A new study reports that four amino acid changes in a single protein help the naked mole rat repair DNA more efficiently. The same rodent can live up to about 37 years in captivity, far longer than similarly sized mammals.
The work centers on a protein called cGAS and comes from teams based in Shanghai, China. The authors tested cells, fruit flies, and old mice to show how this repair boost might help bodies resist age related damage.
The cGAS, an enzyme that detects stray DNA and sparks immune signals, usually helps cells spot viral or damaged DNA. In some mammals, it also shows up in the nucleus, where it can influence how cells respond to breaks in their chromosomes.
In human and mouse cells, nuclear cGAS can slow homologous recombination, an error-free way to mend DNA breaks using a sister copy. The evidence shows cGAS binds PARP1 and blocks a repair complex, thereby stalling fixes and raising mutation risk.
The research was led by Yu Chen from the Tongji University School of Medicine (TUSM). The team coordinated assays across cell types and organisms to connect molecular events to health measures.
In naked mole rats, the same protein behaves differently after damage. It sticks around longer at the break site and helps the cell complete the repair with fewer loose ends.
The group pinpointed four substitutions that reduce ubiquitination, a tag that often marks proteins for removal. Less tagging means cGAS avoids the cellular garbage chute and remains available right when repair crews assemble.
That lingering presence strengthens contacts on chromatin, the DNA and protein package inside the nucleus. With cGAS staying put, the repair scene looks better staffed and better timed.
One of the key connections involved a helper protein called FANCI that assists in organizing the cell's repair team. The altered cGAS strengthened FANCI's partnership with another repair helper, RAD50, which detects broken DNA strands and helps bring the repair machinery to the damaged site more quickly.
The team also delivered the mole rat version into aged mice using an adeno-associated virus (AAV), a small gene delivery virus used in lab studies. Those mice showed lower frailty scores, fewer gray hairs, and fewer cells with senescence markers two months later.
The naked mole rat's survival strategy didn't appear overnight. Its underground lifestyle, low oxygen tolerance, and unusually stable body chemistry all reduce cellular stress, likely allowing evolution to fine-tune DNA repair instead of favoring fast reproduction.
Over thousands of generations, that tradeoff favored genome stability, the ability to maintain DNA integrity under constant environmental pressure.
Researchers think this may reflect a broader rule across species: longer-lived animals often invest more energy in repair and maintenance than in rapid growth.
Similar adaptations have been noted in bats and elephants, whose cells also show elevated DNA repair activity. The mole rat version of cGAS may simply be the clearest example yet of that principle written into protein form.
Scientists already knew that cGAS can be tuned by post-translational modification (PTM), a chemical change added to a protein after it is made.
One report found that changing a single lysine on cGAS shifts its grip on repair partners and can nudge the balance toward repair instead of blockade.
The new study shows evolution found a different route, using four amino acids to adjust the protein's lifetime and partners near a break.
The research revealed that the naked mole rat's version of cGAS plays an unexpected role inside the cell's nucleus, where it appears to help extend lifespan by improving how the cell manages DNA repair and stability.
Repair pathways connect directly to senescence, a permanent slow growth state linked to aging. When DNA breaks linger, cells often flip into senescence and release inflammatory signals that can damage neighboring tissues.
The results are not a blueprint for DIY gene edits or supplements. Turning up a repair pathway without guardrails risks off-target effects, unexpected actions on other molecules or pathways that can trigger new problems.
Healthy systems keep a tight lid on genome stability, the cell's ability to avoid harmful DNA changes. Too much repair at the wrong time can recombine the wrong pieces, create chromosomal rearrangements, or favor tumor growth.
cGAS does more than handle repair and immune sensing. Another study shows its product, cGAMP, a small signaling molecule made by cGAS, can activate a damage response independent of interferon signals. This hints at cross talk that needs careful mapping before any therapy.
The results point to realistic next steps, not instant cures. Researchers will need to test whether a human safe tweak can reproduce the mole rat effect without disrupting immunity or cell cycle control.
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